Posttraumatic stress disorder (PTSD) is a pervasive and debilitating mental disorder in the U.S. population; 1 in 9 women will meet criteria for the diagnosis during their lives. PTSD, the sentinel stress-related mental disorder, has been declared 'a life sentence' based on the belief that the disorder leads to a host of adverse physical health problems. The association between PTSD and coronary heart disease (CHD) has received particular attention, with observational studies suggesting PTSD contributes to early development of CHD, and also that mitigating CHD risk in this population might reduce overall burden of CHD. Despite consistent findings from these studies, whether PTSD causes CHD has not been established and PTSD is not ranked in the American Heart Association (AHA) 2010 impact goals as a risk factor that requires attention. As a result, neither systematic surveillance nor treatment is provided persons with PTSD to reduce potential risk of developing CHD. Informed by these concerns, we propose 3 strategies to address if PTSD is causally related to CHD, using state-of-the-science approaches for inferring causality in observational data. First, we will apply innovative analytic designs not previously been applied in this research area, including consideration of effects when PTSD remits. Second, we will examine if PTSD influences both CHD onset and severity; to date, effects of PTSD on myocardial infarction (MI) severity has only been examined cross-sectionally. Third, evidence that PTSD affects CHD-related behavioral and biological pathways would offer further support for causation but a recent review noted mechanistic evidence on the progression of adverse cardiac outcomes in PTSD is lacking. PTSD is linked with CHD risk related behavior and biomarkers. Because cross-sectional studies cannot test if such behaviors and biomarkers are vulnerabilities for or consequences of PTSD, longitudinal studies are needed. We propose the following Specific Aims: (1) To determine if PTSD influences risk of CHD onset and MI severity with conventional and marginal structural models; (2) To examine whether PTSD changes health behaviors; (3) To identify if PTSD influences biological pathways associated with increased CHD risk. We will examine if new onset of PTSD among CHD-free women, produces changes in novel and conventional biomarkers associated with CHD risk. We will also explore using Mendelian Randomization (MR) to test whether the relation between PTSD and CHD, health behaviors, and CHD risk markers is explained by shared genetic risk or reverse causality. Taken together, the proposed research moves forward not only our understanding of the relation between PTSD and CHD but also the pathophysiology of PTSD in relation to health more broadly and has direct implications for population health.